B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

Abstract

Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development

“…There has been a long‐standing quest to develop axon repair therapies for spinal cord injury and other traumas and diseases of the nervous system. While progress had been quite slow for decades, recent work has demonstrated that extensive repair can indeed be elicited by targeting master regulators of cellular growth that have been widely characterized for their roles in neuronal development, in injured CNS neurons (Liu et al, ; O'Donovan et al, ). These include tumor suppressors and oncogenes, transcription factors, and regulators of various posttranslational modifications.…”

Pim‐1 Expression in Rat Retina and its Changes after Optic Nerve Crush

“…Recent studies have shown that the regulation of the expression of some molecules, such as PTEN in AKT pathway, SOCS3 in JAK‐STAT pathway, and B‐Raf in RAF–MEK pathway, can enhance intrinsic regenerative capacity of RGC after optic nerve injury (Sun et al, ; de Lima et al, ; O'Donovan et al, ; Yungher et al, ), by separately knocking out PTEN or SOCS3 and activating B‐Raf. As a result, these treatments are presumed to promote the survival of RGC and long‐distance regeneration of the optic nerve, reaching the optic chiasma and suprachiasmatic nucleus, even up to the superior colliculus and lateral geniculate body.…”

“…The optic nerve, like the rest of central nervous system, does not regenerate easily after optic nerve crush (ONC). The reasons can be the following: the massive death of the retinal ganglion cells (RGC) induced by caspase dependent apoptotic pathway within 2 weeks (Fischer et al, ; Joachim et al, ), weak intrinsic regeneration ability of RGC (Sun et al, ; O'Donovan et al, ), neurotrophic factor deficiency (Quigley et al, ), or reactive gliosis (Huang et al, ). The massive death of RGC and its inability of intrinsic regeneration are the key determinants in the successful regeneration of damaged optic nerve.…”

Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

“…Recent progress has furthered our understanding of the intrinsic molecular brakes to axon growth and regeneration (Barber et al., 2019; Bray et al., 2019; Chauhan et al, 2020; Koseki et al., 2017; Liu et al., 2017; Sekine et al., 2018; Song et al., 2019; Tedeschi et al., 2016; Tedeschi & Popovich, 2019; Yang et al., 2020; Zhang et al., 2019). It is now possible to reprogram adult mammalian neurons into a growth‐competent state by recapitulating, at least in part, developmental programs (Blackmore et al., 2012; Hilton & Bradke, 2017; Liu et al., 2010; Moore et al., 2009; O'Donovan et al., 2014). However, recapitulation of early developmental programs may proceed at the expense of synaptic specificity, synapse formation and functional connectivity (Carlin et al., 2018; Carlin, Halevi, Ewan, Moore, & Cavalli, 2019; Tedeschi & Bradke, 2017; Wang, Reynolds, Kirry, Nienhaus, & Blackmore, 2015), negatively impacting formation, and consolidation of neuronal circuits.…”